10-lower alkoxy-5h-dibenz [b, f] azepines



United States Patent Ill-LOWER ALKOXY-SH-DIBENZ[b,f]AZEPINES WalterSchindler, Riehen, near Base], and Hans Blattner,

Basel, Switzerland, assignors to Geigy Chemical Corporation, Ardsiey,N.Y., a corporation of Delaware No Drawing. Filed Sept. 11, 1962, Ser.No. 223,300 Claims priority, application Switzerland Nov. 16, 1959Claims. (Cl. 260239) The instant invention concerns new N-heterocycliccompounds.

This invention relates to compounds of formula in which X signifieshydrogen, chlorine, bromine, lower alkyl, or

lower alkoxy,

Y signifies hydrogen, chlorine, bromine or lower alkyl,

and

R signifies lower alkyl.

These compounds are obtained in good yield when compounds of formulaCH=OH in which R signifies lower alkyl and X and Y have the meaningsgiven above, are reacted with bromine, whereby 5-acyl-10,11-dibromo10,11 dihydrodibenz[b,f] azepines of formula Br Br (IJH--(IJH N l (JO-Rn(III) in which X, Y and R have the meanings given above, are obtained,and the dibromo derivatives of Formula III are converted into compoundsof general Formula I by treatment with at least two equivalents of analkali metal lower alkanolate.

In this process, monobromoazepines of formula thus constitute thereaction products. In the Warm, monobromo azepines of Formula IV reactwith alkali metal lower alkanolates to furnish compounds of Formula I,which under the same more drastic conditions are also obtained directlyfrom the dibromo azepines of Formula III. For such conversion of bromoderivatives of either Formulae III and IV, a relatively large excess ofalkali metal lower alkanolate is preferably used, i.e. about 4-10 molper mol of azepine compound, in the alkanol corresponding to that of thealkanolate at or near its boiling temperature. Fairly long reactiontimes, e.g. between 12 and 48 hours, and high concentrations of alkalimetal alkanolate are advised in order to achieve complete reaction. Theacid residue -COR e.g. an acetyl residue, suffers base catalyzedalcoholysis during the process, and an ester, e.g. an alkanol acetate isformed. Such alcoholysis consumes no alkali metal alkanolate and theformation of the compound of Formula I may be regarded as ended when allthe bromine is present as alkali metal bromide.

Suitable lower alkanols for the alkanolate component and solvent are,for example, methanol, ethanol, n-propanol, n-butanol, isobutanol;methanol and ethanol being preferred if the resultingl0-alkoxy-5H-dibenz[b,f]azepines of Formula I are to serve asintermediates.

In the monobromo azepines of general Formula IV, and in thecorresponding deacylated compounds formed during the reaction, thebromine atom is situated on a double bond and would therefore beexpected to be quite inert towards bases such as those employed in thepresent process. The ready replaceability by an alkoxy group istherefore surprising and it is decisive for the success of the process.The resulting compounds of general Formula I have the character ofenol-ethers and are readily hydrolysed to the correspondingketo-oompounds. 10- alkoxy-5H-dibenz[b,f]azepines are useful asantioxidants; they are intermediates for the preparation ofSH-dibenz[b,f]azepin-10(l1H)-ones of the Formula V.

Starting substances of the general Formula II are, for example,S-acetyl-SH-dibenz[b,f]azepine, 5-acetyl-3-chloro-5H-dibenz[b,f]azepine, 5-acetyl-3-bromo-5H-dibenz[b, fJazepine,S-acetyl-3-ethyl-5H-dibenz[b,f]azepine and 5-acetyl-3,7-dichloro-5H-dibenz[b,f]azepine. These compounds may beprepared by acetylation of the corresponding 5H-dibenz[b,f]azepines, butthey may also, and preferably, be prepared directly from thecorresponding 10,11-dihydro-5H-dibenz[b,f]azepines by acetylation,bromination of the N-acetyl derivatives in the 10 position by means ofbromosuccinimide and elimination of hydrogen bromide under conditionswhich do not affect the N-acetyl group, e.g. by means of aqueousalcoholic alkali hydroxide solutions at temperatures between about 20and 50 or, preferably, by means of tertiary organic bases such as hotcollidine.

The following examples illustrate in more detail the operation of theprocess according to the invention. Parts therein mean parts by weight,and these are to parts by volume as g. are to cmfi. The temperatures aregiven in degrees centigrade.

Example 1 (a) 407 parts of bromine in 250 parts by volume of chloroformare dropped into a solution of 600 parts of5-acetyl-5H-dibenz[b,f]azepine in 1200 parts by volume of chloroform at5l0 while stirring. The decolourized solution is then cooled to l0 whilestirring, when crystallisation of the5-acetyl-10,l1-dibromo-l0,l1-dihydro-5H-dibenz[b,f]azepine takes place.It is filtered oif by suction and dried in vacuo. Melting point:136-l38.

(b) 485 parts of the above dibromo compound are dissolved in 1500 partsby volume of dioxan at 40 and the solution is then cooled to 20, when nocrystallisation should occur. A solution of 76 parts of potassiumhydroxide in 342 parts by volume of absolute alcohol is added at 20-25with stirring over a period of 15-25 minutes. The reaction solution issubsequently stirred for approximately 14 hours at room temperature andthen poured into 5000 parts of water. The 5-acetyl-l0-bromo-5H-dibenz[b,f] azepine thereby crystallises out. It is filtered off bysuction and recrystallised from alcohol. Melting point: 109-110".

(c) 157 parts of S-acetyl-lO-bromo-SH-dibenz(b,f) azepine are introducedinto a solution of 50 parts of sodium in 1000 parts by volume ofabsolute alcohol with vigorous stirring, and the solution is then boiledunder reflux for 18 hours. After cooling, the reaction solution whilestirring vigorously is poured into 5000 parts of water, when the crudeproduct is precipitated. It is filtered off by suction and dissolved inether. The ethereal solution is thoroughly washed with water, dried andevaporated. The residue is first fo all recrystallised from alcohol andthen from ligroin, when 10-ethoxy-5H-dibenz- [b,f] azepine of meltingpoint 132-133 is obtained.

10-methoxy-5H-dibenz[b,f]azepine, M.P. 124, 10-nbutoxy-5H-dibenz[b,f]azepine, M.P. 113-114", 10-methoxy-3,Tl-di-chloro-SH-dibenz[b,f]azepine,M.P. 182- 183 and 2-methoxy-10 rnethoxy-SH-dibenz [b,f] azepine aresimilarly obtained.

Example 2 125 parts of the 5-acetyl-10,11-dibromo-10,1l-dihydro-5H-dibenz[b,f]azepine prepared according to Example 1(a) are introducedinto a solution of 135 parts of sodium methylate in 1,000 parts byvolume of distilled methanol and the whole is boiled under reflux withstirring for 16 hours. Approximately 500 parts by volume of methanol arethen distilled off and the remaining reaction mixture is boiled for afurther 24 hours under reflux. After cooling, 500 parts of water areslowly added, the precipitated crystals are filtered off with suction,washed thoroughly with water and dried in vacuum at 60. They are thenrecrystallised from 350 parts by volume of absolute ethanol and theIO-methoxy-SH-dibenz- [b,f]azepine of melting point 124 is obtained.

This application is a continuation-in-part of our pending patentapplication Serial Nos. 69,302 and 156,- 551, filed on November 15,1960, and November 8, 1961, respectively, and both now abandoned.

H-dibenz[b,f]azepine-10(11H)-ones of the general Formula V t H (V)wherein X and Y have the meanings given with Formula I, are obtained ingood yield from -alkoxy-5H-dibenz- [b,f] azepines of Formula I byheating these for a short time, e.g. from 5 to minutes in 0.55 N aqueousmineral acid, e.g. hydrochloric, sulfuric or phosphoric acid,

5H-dibenz[b,f]azepine-10(l1H)-ones of Formula V are active asantioxidants.

Important compounds of general formula I are, e.g. 10- methoxyor10-ethoxy-5H-dibenz[b,f] azepine, their 3- chloro-, 4-bromo,3-ethyl-3,7'-dimethyland 3,7-dichloroderivatives, such IO-methoxyand10-ethoxy-compounds being preferred. Further compounds of Formula I aree.g. the 10-propoxy-, 10-isopropoXy-, l0-butoxyand 10-amyloxy-derivative of 5H-dibenz[b,f]azepine and its 3- chloro-, 3-bromo,3,7-dichloro, 3,7-dimethyland 3-ethylderivative. Preferred acids for thehydrolysis according to the invention are hydrochloric andtrichloracetic acid.

The following examples illustrate in more detail the process whereby thecompounds of Formula I are converted to those of Formula V. Partstherein mean parts by weight, and these are to parts by volume as g. areto cm. The temperatures are given in degrees centigrade.

Example 3 2 parts of l0-ethoxy-5H-dibenz[b,f]azepine are suspended in 20parts by volume of 2 N hydrochloric acid and boiled under reflux for 10minutes, when the suspended substance first of all liquefies and thenbecomes solid again. The reaction mixture is cooled, and the crude5H-dibenz[b,f]azepine-10(1lH)-one is filtered off by suction and washedwith water until neutral. After recrystallisation from alcohol it meltsat -146.

The 3,7 dichloro-5H-dibenz[b,f]azepine 10(11H) one of melting point318-320 is similarly obtained from 10- methoxy-3,7-dichloro-5H-dibenz[b,f] azepine.

What we claim is:

1. A compound of the formula wherein X is a member selected from thegroup consisting of hydrogen, chlorine, bromine, lower alkyl and loweralkoxy,

Y is a member selected from the group consisting of hydrogen, chlorine,bromine and lower alkyl, and R is lower alkyl' 2.10-ethoxy-5H-dibenz[b,f]azepine.

3. 10-methoxy-SH-dibenz[b,f]azepine.

4. 10-n-butoxy-SH-dibenz[b,f] azepine.

5. 10-methoxy-3,7-dichloro-5H-dibenz[b,f]azepine.

No references cited.

1. A COMPOUND OF THE FORMULA